Current Endocrine Treatment in Breast Cancer—
Breast cancer continues to affect one woman in ten in the western world, and despite significant treatment advances in recent years, the mortality rate still remains at around 35%. Current endocrine therapies are based on manipulating the estrogen receptor (ER) either directly with ER modulators such as tamoxifen, or by reducing levels of circulating estrogen with aromatase inhibitors (AIs). The development of third-generation aromatase inhibitors (AIs) has changed therapy in post-menopausal patients with hormone-sensitive breast cancer. There are two main types of AIs: irreversible steroidal inhibitors exemplified by exemestane, and non-steroidal inhibitors such as anastrozole and letrozole which are competitive reversible inhibitors. Randomized clinical trials, including several led by our group, have demonstrated prolongation of disease-free survival in patients with early stage breast cancer.
Regardless of the age of the patient, adjuvant endocrine therapy offers substantial benefit in terms of reduction in risk of tumour recurrence in women with ER-positive tumours. However, while most patients initially respond to tamoxifen, in 30-40% of cases these tumours have metastatic disease within 5 years. This common clinical scenario precipitates cessation of the regime and the initiation of second line therapy. Uncovering the key mechanisms involved in the development of metastasis provide predictive markers of disease recurrence which will enable the tailoring of existing therapies and the development of new drugs in this class, to improve outcome in specific patient groups.
Biomarkers of Endocrine Sensitivity in Breast Cancer Patients—
Classic pathologic parameters, such as tumour size, grade, ER and HER2 status have been invaluable in informing the clinical management of breast cancer; however, a significant number of patients with a good prognostic profile will have a tumour recurrence. More recently, with the advent of gene expression profiling research, additional mechanisms to predict disease recurrence are now available. Technologies provided by Agendia (MammaPrint) and Genomic Health (OncotypeDx) which involve detection of a panel of genes performed by the providing companies have reported independent hazard ratios of 2.23 and 3.21 respectively. The predictive value of these tests is greater than any of the currently employed pathological parameters including ER and HER2 (hazard ratios 0.665 and 1.505, respectively). Elucidation of the mechanisms of how a tumour can adapt to endocrine therapy and consequently reoccur will provide mechanistically anchored predictive biomarkers, which can easily be detected and used in the clinic to select appropriate treatments.
New Therapeutics for the Treatment of Metastatic Disease
There are no targeted therapies currently available that act to specifically inhibit metastasis in breast cancer. Most patients are treated with chemotherapy or radiotherapy which does not specifically target cancer cells. Classic DNA-damaging cytotoxic drugs (eg. cyclophosphamide, doxorubicin, 5-fluorouracil) are still in the mainstay of treatment regimes, and, although crude, are effective. Current directed therapies against metastatic cancers only inhibit angiogenesis. In doing so, they cut off nutrient supply and inhibit access of metastatic cells to the blood stream. The anti-angiogenic, AVASTIN® (bevacizumab) (Roche) is used to treat a range of cancers, including colorectal, lung, and kidney cancer. Its use in metastatic breast cancer however is controversial. The FDA recently withdrew approval for its use in the metastatic setting and the European Commission has only approved it in combination with the chemotherapy drugs Paclitaxel or XELODA® (capecitabine). There is therefore a pressing need in terms of healthcare and economics to develop new directed therapies to treat metastatic breast cancer.
It is an object of the invention to overcome at least one of the above-referenced problems.